Sensitive and selective method and device for the detection of trace amounts of a substance

ABSTRACT

A piezoelectric crystal element and a sensor utilizing the same are presented for use in a sensor device for identifying at least one foreign material from environment. The crystal element comprises at least one crystal resonator in the form of an inverted mesa structure, which has a membrane-like region and has a certain resonance frequency value. A surface region of the crystal resonator is modified by reactive molecules of a kind capable of interacting with the foreign material to yield a reaction product that effects a change in the resonance frequency of the crystal resonator from said certain resonance frequency value. This change is indicative of the identity and quantity of the foreign material.

FIELD OF THE INVENTION

This invention is in the field of mass detection using a coatedpiezoelectric sensor.

BACKGROUND OF THE INVENTION

In recent years there has been a growing interest in coatedpiezoelectric crystals, not only as highly sensitive and selectivedetector of various air pollutants but also as simple, inexpensive andportable device. The high sensitivity and simple relationship betweenmass and frequency make the quartz crystal microbalance as an ideal toolfor the study of adsorption and as a selective chemical sensor in manyapplications.

The principle of the detection is that the frequency of vibration of anoscillating crystal is decreased by the adsorption of a foreign materialon its surface. A gaseous pollutant is selectively adsorbed by a coatingon the crystal surface, thereby increasing the weight of the crystal anddecreasing the frequency of vibration. The decrease in the frequency isproportional to the increase in weight due to the presence of gasadsorbed on the coating according to the following equation: ΔF=K·ΔC.Here, ΔF is the frequency change (Hz), K is a constant which refers tothe basic frequency of the quartz plate, area coated, and a factor toconvert the weight of injected gas (g) into concentration (ppm), and ΔCis concentration (ppm) of sample gas.

U.S. Pat. No. 3,164,004 teaches that a piezoelectric quartz crystalcoated with a substrate selectively sensitive to changes in theatmospheric environment can serve as a detection device in fluidanalyzers. In general, this discovery is based on the principle that theoscillation of a crystal, both in frequency and amplitude, is in part afunction of its weight. The change in weight of a crystal coated with asubstrate selectively sensitive to a particular contaminant when placedin an environment containing that contaminant is, in turn, at leastpartly a function of the concentration of the contaminant. Therefore,the measurement of the change in oscillation characteristics of a coatedcrystal sensitive to a particular contaminant upon exposure to a givenatmosphere is a direct and highly sensitive measure of the presence andconcentration of that contaminant. Variations of and improvements inthis basic method are shown, inter alia, in the following publicationsU.S. Pat. No. 5,177,994; U.S. Pat. No. 5,817,921, and U.S. Pat. No.6,085,576; Japanese Patents Nos. 1244335, and 5187986; European PatentNo. 992768, and “Electronic Nose and Artificial neural Networks”, L. Moyand M. Collins, American Chemical Society, Anal. Chem., 1986, 58, pp.3077–3084; “Piezoelectric Crystal Sensor for the Determination ofFormaldehyde in Air”, Talanta, Vol. 38, No. 5, pp. 541–545, 1991; “OdorSensing System Using Neural Network Pattern Recognition”, ToyosakaMoriiznmi and Takamichi Nakamoto, International Conference on IndustrialElectronics, Control, Instrumentation and Automation, Nov. 9–13, 1992,Marriot Mission Valley, San Diego, USA.

A sensor has two equally important requirements: sensitivity andselectivity. There are two ways of achieving high selectivity andspecificity towards xenobiotic (non-self) agents as we can learn fromnature: (i) the immune system, in which a unique sensor (i.e. antibody)is being synthesized for any invader (i.e. antigen). This is a verycomplicated mechanism that involves a spontaneous constant synthesis ofnew molecules that are examined to fit the antigen; (ii) the olfactorysystem, in which a huge array of receptors are located in the nose insuch a way that a molecule entering the nose interacts with some of thereceptors; the brain then translates the pattern of the signals to anodor. In this case the odor can be a single molecule or a composition ofseveral different molecules.

The combination of a number of sensors and a pattern recognition routineis known as an “electronic nose”. Using the combination of chemicalsensors, which produce a fingerprint of the vapor or gas, therecognition algorithms can identify and/or quantify the analytes ofinterest. The electronic nose is capable of recognizing unknown chemicalanalytes, odors, and vapors. In practice, an electronic nose ispresented with a substance such as an odor or vapor, and the sensorconverts the input of the substance into a response, such as anelectrical response. The response is then compared to known responsesthat have been stored previously. By comparing the unique chemicalsignature of an unknown substance to “signatures” of known substances,the unknown analyte can be determined. A variety of sensors can be usedin electronic noses that respond to various classes of gases and odors.

A wide variety of commercial applications are available for electronicnoses including, but not limited to, detection of explosives or drugs,environmental toxicology, biomedicine, such as microorganismclassification or detection, material quality control, food andagricultural product monitoring, ambient air monitoring, employeeprotection, emissions control, and product quality testing. Referring tothe detection of explosives, a number of laboratory techniques for thedetection of explosives are known, using gas chromatography, massspectrometry, ion mobility spectroscopy, NMR, plasma chromatography andvisible chromatography. While some of these techniques are capable ofppb detection, the detection systems need elaborate techniques foroperation, are usually not portable and simple, and are thus not usefulfor field use.

SUMMARY OF THE INVENTION

There is a need in the art for a sensing device that is compact, capableof detecting trace amounts of mass of 10⁻¹⁵ g order and even less, thatis useful in a broad variety of applications and can respond accuratelyto a broad variety of gases, analytes, odors and fluids.

The present invention provides a sensing device (also referred to as anelectronic-nose device) that is compact and, in certain embodiments,configured to be a handheld device. The device can be used to measure oridentify one or more analytes in a medium such as vapor, liquid or gas.

The main idea of the present invention is based on the use of apiezoelectric crystal element (such as quartz, ceramics), which, on theone hand, can be manufactured by the existing techniques to be mountablein a sensor device, and, on the other hand, has a sufficiently thin(membrane-like) region, which defines a sensing region of the crystalelement, thereby providing increased sensitivity as compared to theknown sensors.

The crystal element, according to the present invention, is in the formof the so-called “inverted mesa structure”, in which a relatively thinmembrane-like region (resonator) is surrounded by relatively thick endregions of the crystal element. A pair of electrodes are located on theopposite sides of this membrane-like region. The electrodes and/or themembrane-like region have a surface region coated with reactivemolecules, thereby presenting a sensing region of the deviceelectrically excitable by the environment (which can be gas or liquid).The reactive coating molecules interact with a foreign material from theenvironment to yield a reaction product that effects a change in theresonance frequency of the crystal resonator from a certain resonancefrequency value characterizing said crystal resonator.

The reactive coating molecules are preferably organized in aself-assembled monolayer (SAM) formed on the surface of the electrodesand/or the membrane-like region (i.e. on the surface of a substrate).The monolayer consists of receptor compounds comprising a linker thatconnects said compound to the surface of said substrate, an optionalspacer, a structural element and an active head group.

There is thus provided according to one aspect of the present invention,a piezoelectric crystal element for use in a sensor device foridentifying at least one foreign material from environment, the crystalelement comprising at least one crystal resonator in the form of aninverted mesa structure having a membrane-like region, which issubstantially thinner as compared to end portion of the crystalresonator surrounding said membrane-like region and has a certainresonance frequency value, a surface region of said at least one crystalresonator being modified by reactive molecules of a kind capable ofinteracting with said at least one foreign material to yield a reactionproduct that effects a change in the resonance frequency of saidmembrane-like region from said certain resonance frequency value, saidchange being indicative of the identity and quantity of said at leastone foreign material.

According to another aspect of the present invention, there is provideda piezoelectric sensor for use in a device for identifying at least oneforeign material from environment, the sensor comprising a piezoelectriccrystal element having at least one crystal resonator in the form of aninverted mesa structure defining a sensing membrane-like region which issubstantially thinner as compared to end portion of the crystalresonator surrounding said membrane-like region and has a certainresonance frequency value, and electrodes formed on opposite sides ofsaid sensing membrane-like region, said at least one crystal resonatorhaving a surface region modified with molecules capable of interactingwith at least one foreign material from the environment to which thecrystal resonator is exposed to yield a reaction product that effects achange in the resonance frequency of said membrane-like region from saidcertain resonance frequency value, said change being indicative of theidentity and quantity of said foreign material.

The input and output of the sensor is connectable to a control meansoperable for actuating the at least one crystal resonator and measuringthe change in the resonance frequency, to generate measured datarepresentative of the identity and quantity of said foreign material.

The metal electrodes used in the sensor may comprise a metal selectedfrom Au, Pt and Al, with Au being the most preferred metal. The modifiedsurface region may include the surface of the membrane region, thesurface of the respective electrode, or both.

The control means comprises an actuator utility (either a commonoscillator for all the crystal resonators or a plurality of oscillatorseach associated with a corresponding one of crystal resonators, and oneor more switches depending on the number of crystal resonators) and adetector utility. The actuator utility actuates said at least onecrystal resonator to put it in operation. The detector utility comprisesan electronic circuit for detecting the frequency of the at least onecrystal resonator to enable measurement of said change.

According to yet another aspect of the present invention, there isprovided a piezoelectric sensor device for identifying at least oneforeign material from environment, the device comprising:

-   (i) a sensor including a piezoelectric crystal element having at    least one piezoelectric crystal resonator in the form of an inverted    mesa structure defining a sensing membrane-like region, which is    substantially thinner as compared to end portion of the crystal    resonator surrounding said membrane-like region and has a certain    resonance frequency value, and having electrodes formed on opposite    sides of said sensing membrane-like region, said at least one    crystal resonator having a surface region modified with molecules    capable of interacting with a foreign material of the environment to    yield a reaction product that effects a change in the resonance    frequency of said at least one membrane-like region from said    certain resonance frequency value, said change being indicative of    the identity and quantity of said foreign material; and-   (ii) a control means operable for actuating said at least one    crystal resonator, measuring the change in the resonance frequency,    and generating measured data representative of the identity and    quantity of said foreign material.

Preferably, the crystal element comprises an array of spaced-apartcrystal resonators, each in the form of the inverted mesa structureformed with a pair of electrodes at opposite surfaces of themembrane-like region, thereby defining an array of sensing regionsaffectable by the environment. The surface regions of different crystalresonators are modified with different reactive molecules, therebyenabling the detection of various foreign materials contained in theenvironment. Au electrodes, for example, are suitable for modificationwith sulfa containing molecules. When the quartz membrane regionparticipates in the sensing operation, then the quartz may be modifiedby different functional groups, such as, for example, silanes.

The crystal element may comprise the so-called “reference” or “passive”crystal resonator (without coating) which is screened from theenvironment. The change of the resonance frequency of the “active”crystal resonator caused by the foreign material is thus determined as adifference between the resonance frequencies of the active and passiveelements. Alternatively, such reference data (or the certain value ofthe resonance frequency characterizing the crystal resonator) may bestored in a memory of the control means.

Preferably, the crystal resonators are equally distanced from theactuator utility (oscillator). This may be implemented by arranging theresonators (wherein one of the crystal resonators may be the referenceor passive element) in spaced-apart relationship along a circular pathand placing the common oscillator either in the center of the circle orat any other location at the central axis of the circle. Thus, thecrystal element may comprise a disc carrying the circular array of theequally spaced piezoelectric crystal resonators, and the actuatorutility located on the central axis of the disc. It should be understoodthat the entire disc may be made of a piezoelectric crystal, in whichcase the crystal is patterned to define the circular array ofspaced-apart inverted mesa structures (i.e., the circular array ofmembrane-like regions defining the sensing regions). In another examplesof the invention, the plurality of oscillators are placed on the disccarrying the plurality of crystal resonators, and all the crystalresonators are equally distanced from their respective oscillators.

According to yet another aspect of the present invention, there isprovided a piezoelectric sensor device for identifying at least oneforeign material from environment, the sensor device comprising:

an array of spaced-apart crystal resonators, each crystal resonatorbeing in the form of an inverted mesa structure having a membrane-likeregion, which is substantially thinner as compared to end portion of thecrystal resonator surrounding said membrane-like region and has acertain resonance frequency value, each of the crystal resonators beingexcitable by the environment to cause a change in the resonancefrequency thereof from said certain resonance frequency value; and

an actuator utility for operating the crystal resonators, said actuatorutility being arranged such that each of the crystal resonators isspaced the same distance from its associated oscillator of the actuatorutility.

The modification of the surface region of the crystal resonator may beachieved by two alternative techniques: (1) construction of organized,self assembled monolayers (SAM); or (2) formation of polymeric layer.

The organized, self-assembled monolayer (SAM) consists of receptorcompound comprising a linker that connects said compound to the surfaceof said substrate, an optional spacer, a structural element and anactive head group.

Relating to the formation of a polymeric layer, the preferred technologyfor forming a polymer layer in a controlled manner is byelectropolymerization.

It should be noted that the device of the present invention could beused in gaseous medium, liquid medium or a combination thereof, thusacting as an electronic nose and/or as an electronic tongue. Anelectronic tongue is a device similar to the electronic nose, butcapable of operating in a liquid medium, and enables the analysis ofsolutes in a solution. Such a combined device provides for simultaneousanalysis of a solution and it's vapors, providing a complete picture ofthe detected material.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, a preferred embodiment will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIGS. 1A and 1B are schematic illustrations of two examples of a sensordevice according to the invention;

FIGS. 2A to 2C more specifically illustrate a crystal resonator in apiezoelectric crystal element of the device of either of FIGS. 1A and1B;

FIGS. 3A to 3C illustrate experimental results of the absorption ofthree different analytes: musk in ethanol, TATP and TNT;

FIGS. 4A and 4B are block diagrams of the devices of FIGS. 1A and 1B,respectively, showing more specifically a control means of the device;and

FIG. 5 schematically demonstrates the principles of modification of themetal surface of an electrode in the crystal resonator of either one ofFIGS. 2A and 2B by utilizing the construction of organized,self-assembled monolayers (SAM).

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIG. 1A, there is illustrated a sensor device 10A accordingto the invention, which, in the present example, is implemented as adisc-shaped printed circuit board 12. The device 10 comprises such mainconstructional parts as sensor comprising a piezoelectric crystalelement (quartz crystal in the present example), and a control means.

The crystal element may comprise one or more crystal resonators, eightsuch resonators CE₁–CE₈ made of quartz crystal being shown in thepresent example. The control means comprises electronic components,which are incorporated in the disc 12 and include an actuator utility14A, and a detector utility, generally at 15. The actuator utility 14Ais composed of an oscillator, and a plurality of switches associatedwith the crystal resonators, respectively, as will be described morespecifically further below with reference to FIG. 4A.

The quart crystal resonators CE₁–CE₈ are arranged in a spaced-apartrelationship along a circular path centered around the actuator utility14A. This arrangement equally distances all the quartz crystalresonators from the oscillator. It should be understood that the samecan be achieved by placing the oscillator at any location on the centralaxis of the circle formed by the array of equally spaced quartz crystalresonators.

It should be noted, although not specifically shown, that one of thecrystal resonators may be a reference one screened from the environment,to which the other “active” resonators are exposed. The provision ofsuch a reference crystal resonator is optional, and may be replaced bythe storage of a reference signal in a memory of the control means.

FIG. 1B exemplifies a sensor device 10B according to the invention. Tofacilitate understanding, the same reference numbers are used toidentify the common components in the devices 10A and 10B. The device10B thus differs from the device 10A in the construction of an actuatorutility 14B, which utilizes several oscillators—eight oscillatorsOS₁–OS₈ in the present example each associated with a corresponding oneof eight crystal resonators CE₁–CE₈. Separate operation of each crystalresonator by its associated oscillator allows for increasing the numberof crystal resonators in the matrix (practically with no limitations forthe number of crystal resonators). Here, similar to the device 10A, thesymmetry of accommodation of the crystal resonators is maintained, i.e.,each of the crystal resonators is spaced the same distance from therespective oscillator.

Turning now to FIGS. 2A–2C, each of the quartz crystal resonators is aninverted mesa structure 16 defining a membrane-like region 18 having athickness of about several micrometers. To fabricate such an invertedmesa structure, a crystal is patterned either at one side thereof toform one recess (FIG. 2A), or at both opposite sides thereof to form twoopposite recesses (FIG. 2B), thereby forming the membrane central region18 of a sufficiently small thickness (to obtain desirably highsensitivity of the sensor device) between two relatively thicker endportions of the structure surrounding the membrane-like region. Metalelectrodes 20A and 20B (made from Al, Pt or Au) are deposited ontoopposite surfaces of the membrane-like region 18. As shown in theexample of FIG. 2C (illustrating a crystal element with a singleresonator), the crystal element is supported by a holder 21. Preferably,Au-based glue is used for attaching the crystal element to the holder.

The active quartz crystal resonator is formed with a surface region 22(exposed to the environment) modified by reacting molecules intended tointeract with one or more specific foreign materials that may be presentin the environment. In the present example, this is implemented bycoating the electrodes 20A and 20B with such a molecule, as will bedescribed more specifically further below. It should, however, be notedthat, generally, such a modified surface region may include the surfaceof the electrodes (or only one electrode located on that side of thedevice by which it is exposed to environment), the surface of themembrane-like region, or both. An interaction between these moleculesand one or more specific foreign material affects the frequency ofvibration of the crystal resonator to change from the certain resonancefrequency value. This change is detected by the corresponding electroniccomponent of the control means.

As indicated above, the principle of the detection is that the frequencyof vibration of an oscillating crystal is decreased by the adsorption ofa foreign material on its surface. A foreign material, for example agaseous pollutant is selectively adsorbed by the coating (on the crystalsurface or/and on the metal electrode surface coating the crystalsurface), thereby increasing the weight of the crystal aid decreasingthe frequency of vibration. The decrease in the frequency ΔF (Hz) of thecrystal resonator is proportional to the increase in its weight due tothe presence of foreign material absorbed on the coating and isrepresented by the following equation: ΔF=K·Δm, where Δm is the changein mass per unit surface area and K is a constant which refers to thebasic frequency of the piezoelectric crystal plate.

It should be understood that what is actually detected by the device ofthe present invention utilizing several crystal resonators is theso-called “electronic image” or pattern of the intensities and shape ofresponse of each of the crystal resonators in the crystal element. Theseresponses are indicative of the decay of the vibrating frequencies ofthe crystal resonators caused by the absorption of foreign materials.FIGS. 3A to 3C illustrate experimental results in the form of threedifferent measured patterns (electronic images), respectively, of theabsorption of three different analytes: musk oil in ethanol, TATP andTNT.

FIG. 4A illustrates a block diagram of the sensor device 10A, showingthe main components of the control means 30A for operating andprocessing the response of (n−1) active quartz crystal resonatorsCE₂–CE_(n) utilizing a reference (passive) quartz crystal resonator CE₁.The actuator utility 14A of the control means 30A comprises n switches,which, by n input ports thereof, are connected to the n quartz crystalresonators CE₁–CE_(n), respectively, and by the output ports thereof,are connected to the input port of an oscillator OS. The switches, byother input ports thereof, are connected to a pulse distributor 31. Theoscillator's output is connected to one input port of a double balancedmixer 32, the other input port of the mixer 32 being connected to theoutput port of a reference oscillator 34. The output port of the doublebalanced mixer 32 is connected to the input of a band-pass filter 36,whose output port is connected to the input of a level converter 38,which, in turn, is connected by its output port to the input of afrequency meter 40. All the outputs of the frequency meter 40 areconnected to the respective inputs of a frequency decoder matter fixingdevice 42. The other input ports of the device 42 are connected tocorresponding output ports of a synchronizing and control circuit 44,whose output ports are connected to the inputs of the pulse distributor31.

FIG. 4B illustrates a block diagram of the sensor device 10B showing themain components of the control means 30B. Similarly, to facilitateunderstanding, the common components in the control means 30A of FIGS.4A and 30B of FIG. 4B are identified by the same reference numbers. Asshown, the control means 30B utilize the actuator utility 14B includingn oscillators OS₁–OS_(n), each associated with a corresponding one ofthe crystal resonators CE₁–CE_(n).

The operation of the sensor device 10A (or 10B) is based on the creationof an electronic image of a certain foreign material and theidentification of this material by means of neural network algorithmsutilizing an image processing (pattern recognition) technique. Theelectronic image of a foreign material is created by measuring andanalyzing the relative change of frequency of each quartz crystalresonator (i.e., membrane-like region) during the period of creation ofthe electronic image, as a combination of data generated by all quartzcrystal resonators. The relative frequency change of each quartz crystalresonator corresponds to the changes of various conditions affecting theresonator. As described above, the frequency of the quartz crystalresonator is affected by the presence of a foreign material, as well asby changes in the environmental parameters. In order to reduce theeffects of the environmental parameters up to a minimal value, thereference resonator CE₁, which is insensitive to the foreign material,is used.

The time period of the electronic image creation is defined by thesynchronizing and control circuit 44. The electronic image is composedof a preset number of information packages, each package including agiven number of measurement cycles. Each cycle is defined by the pulsedistributor 31, by means of sequential connection of the resonatorsCE₁–CE_(n) to the oscillator OS through the respective switches (FIG.4A), by switching of oscillators OS₁–OS_(n) via switches (FIG. 4B) orconnecting the outputs of the oscillators OS₁–OS_(n) to the input of thedouble balanced mixer 32 via respective switches (FIG. 4B).

When the quartz crystal resonator is connected to the oscillator, thelatter is excited at the resonance frequency of the resonator, and theoscillator generates a corresponding signal. This signal inputs thedouble balanced mixer 32, which also receives a reference signal fromthe reference oscillator 34. The use of the mixer 32 enables to extracta signal of the relative frequency change, while keeping the parametersand the frequency changes profile unchanged, thereby enabling to reducethe measurement time and increase the accuracy of the sensor device. Theband-pass filter 36 reduces the level of effects caused by theconversion up to a required value. An output signal of the filter 36 issupplied to frequency meter 40 through the level converter 38. Thecircuit 40 carried out frequency measurement, and a signalrepresentative of a measured frequency value, simultaneously withinformation about the number of the respective quartz crystal resonator,cycle and package for the data formation supplied from the synchronizingand control circuit 44, enter the device 42. When the time of theelectronic image formation expires, the information packages aremathematically processed, the foreign material is identified and anoutput signal indicative thereof is generated, being appropriatelyformatted in accordance with the user requirements.

The following table presents experimental results showing the gas sensorsensitivity of various crystal resonators characterized by differentquartz crystal frequencies due to different values of the membranethickness.

Frequency (MHz) 9 30 150 250 300 500 Membrane Thickness 185 56 11 6.75.6 3.3 (μm) Sensitivity (g) 1 × 10⁻⁹ 9.7 × 10⁻¹¹ 1.5 × 10⁻¹³ 2.2 ×10⁻¹⁴ 2.4 × 10⁻¹⁵ 4.2 × 10⁻¹⁶

The modification of the metal surface of the electrode may be achievedby two alternative techniques: (1) construction of organized, selfassembled monolayers (SAM); or (2) formation of polymeric layer. Thesetechniques are described hereinbelow:

(1) Construction of Organized SAM

The use of a piezoelectric substance such as quartz crystals covered atleast partially with a metallic electrode (either gold, platinum oraluminum) provides an essential tool for the construction of organizedorganic monolayers. This is so due to the presence of an organizedmetallic layer that chemically differs from its surrounding enables theselective modification of that part with a suitable functional group. Agold or platinum electrode, for example, can be modified by sulfurcontaining molecules such as thiols, disulfides (either linear orcyclic) or thioethers. Aluminum electrodes can be modified by acidicmoieties such as carboxylic acids and sulfonic acids.

The concept of SAM allows us to prepare tailor made organic moleculesdesigned to act as artificial receptors, each binding selectively to ananalyte to be detected. However, it is important to note that theartificial receptors are designed such that their interactions with ananalyte are of moderate strength, leading to a reversible interaction(i.e. interaction that will enable to use the detector more than once).The artificial receptor according to the present invention comprises alinker that connects the receptor to the surface of the electrode and/orof the crystal resonator, an optional spacer, a structural element (thestructural element and the optional spacer determine the 3D structureand length of the whole monolayer) and an active head group. Thisarrangement is schematically demonstrated in FIG. 5 for a selectivereceptor molecule prepared on the surface of an electrode.

Such a modular design is the basis for an united arsenal of surfacemodifications.

The linker is the element that connects the selective receptor moleculeto the surface of the electrode and/or the resonator and controls thecoverage and smoothness of the monolayer. When the quartz resonators areused with a gold electrode, the linker is based on sulfur-containingcompounds, for example thioethers, disulfides or thiols.

When a spacer is included in the receptor molecules, it may fulfil oneor more of the following roles:

-   (i) To solve synthetic problems of connecting moieties that do not    fit by means of functional groups. This is done by using    bifunctional spacers such as bromo-acids, diamines etc.-   (ii) To control the flexibility of the molecule.-   (iii) To introduce some chiral discrimination when a chiral spacer    is used.

The structural elements are based on molecules which promote the strongpacking of the layers. Examples of such molecules are aromaticmolecules, e.g. phenyl, naphthyl or larger rings, that may be optionallysubstituted by at least one substituent, or amino acids optionallysubstituted that might stabilize the monolayer through hydrogen bonds.The substituents may be of various structures, e.g. electron withdrawingor electron donating groups, depending on the characteristics of theforeign substance to be detected.

The head groups may interact with a specific foreign substance byvarious mechanisms, for example by forming a chemical bond or bycreating a transition state resulting from weak interactions betweencompatible moieties, depending on the characteristics of the substanceand the head group. Examples of head groups are amino, nitro, hydroxyl,thio, thiol, carboxyl and carboxyl derivatives.

Examples of chemical reactions are between functional groups such ascarbazido groups and ketones to form Schiff bases (imines) or betweenboronic acids and diols to form boronic esters.

Except for the functional groups, the head group may also bear varioussubstituents that affect the electron density of this element, thusaltering the strength of the chemical bond or interaction between themonolayer and the substance to be detected.

Several groups of artificial receptors with varying head groups havebeen prepared:

The following compounds are novel and constitute a further aspect of theinvention:

The above compounds may be prepared by known synthetic routes. Forexample, the compounds of Group D (when, q=0, X=O, R⁴=N(CH₃)₂) may beprepared by two alternative synthetic pathways (Method I and Method II)as follows:

The electronic nose of the invention has potential use for the detectionof hidden explosives. The chemical structures of some importantexplosives that are widely used by terrorists, including TATP(triacetone triperoxide) are shown hereinbelow:

(2) Formation of Polymeric Layer

As already mentioned above, the modification of the metallic surface ofthe electrode can be achieved by two alternative ways, by SAM formationor by polymeric layer formation. Relating to the formation of apolymeric layer, the preferred technology for forming a polymer layer ona metallic surface in a controlled manner is by electropolymerization.

The following polymeric layers were produced and examined for adsorbingexplosives: polypyrrole, polythiophene, polytriphenylene,poly(dimethylamino)pyrrole, polypyrene, polyfluorene, polyfluoranthene,polyaniline, poly(N-phenyl)aniline, poly(N-methyl)aniline andpolyfluoroaniline.

The present invention is now described by the following non-limitingexamples:

EXAMPLES Example 1 General Procedure for the Preparation of a Monolayer

A quartz crystal resonator provided with a pair of gold electrodes onboth surfaces thereof was treated with a solution of an sulfur molecule(0.1 mM in absolute ethanol) for 12 hours at 60° C. The resonator wasthen soaked for 30 min in ethanol, first at 60° C. and then at 30° C.,afterwards in acetone for 20 min. at 30° C. three consequent times anddried at 60° C. for 1 hour. The thickness of the reactive monolayerformed is estimated by the change of the resonator frequency,considering also other parameters such as the electrode diameter and thequartz' density. The practically used equation for 300 MHz resonators isas follows:

${\Delta\; h} = \frac{{- \Delta}\; f}{{{- 2.07} \cdot 10^{11}}\rho}$where Δh is the thickness of coating (Å); Δf is the difference infrequency (Hz) (coated vs. uncoated); ρ is the density of coating(g/cm³), and the coefficient (−2.07·10¹¹) presents the effect of theelectrode diameter and the quartz' density. The value of ρ is estimatedto be 1.3 (according to literature).

Example 2 Preparation of Polyaniline on Quartz Resonator

A thin layer of polyaniline on quartz resonator provided with goldelectrodes was prepared by two alternative methods:

-   1. By electropolymerization of an aqueous solution of 0.1M    aniline+1M methansulfonic acid, using a potential cycling at    0–0.85V(vs. Ag/AgCl, KCl sat.) range; followed by rinsing in water    and drying at 60° C.-   2. By a two steps method: a) pretreatment of the resonator with an    ethanolic solution of 0.001M 4-aminothiophenol for 18 hrs. at room    temperature; followed by rinsing in ethanol and water, to form on    the resonator surface a layer of 4-aminothiophenol; b)    Electropolymerization of the product obtained in step a) in an    aqueous solution of 0.1M aniline+1M methansulfonic acid, using a    potential cycling at 0–0.85V(vs. Ag/AgCl, KCl sat.) range; followed    by rinsing in water and drying at 60° C.

In the second method the polymerization is carried out on a preformedlayer of 4-aminothiophenol in order to increase the stability of theformed polymeric layer and its uniformity

Example 3 Synthesis of Compound (4)

First Step:

Triphenylmethanethiol (1.148 g, 0.00415 mol) was dissolved in THF (25 mldried over basic alumina). Freshly prepared 2N NaOMe (2.3 ml) was addedand the reaction mixture was stirred for half an hour.1,3-Dibromo-2-propanol (0.19 ml, 0.0015 mol) was added and the reactionmixture was stirred for four hours at ambient temperature and thenbrought to reflux and heated for additional three hours. Aftercompletion of the reaction, hexane was added and the organic layer waswashed with aqueous methanol (30% methanol), dried over anhydrous sodiumsulfate, and concentrated. Flash chromatography withhexane:dichloromethane (6:4) as eluent afforded the product (1 g, 77%).

1H NMR (250 MHz) δ ppm: 2.1 (d, 1H, J=4 Hz, CH(OH)), 2.3 (m, 4H, CH₂),3.0 (m, 1H, CH(OH)), 7.4 (m, 30H, Ar).

Second Step:

4-Dimethylamino benzoic acid (0.2 g, 0.0012 mol) was stirred with oxalylchloride (1 ml, 0.012 mol) in dichloromethane (10 ml, dried over basicalumina) with one drop of DMF at room temperature for 4 hours. Thesolvent was evaporated. The residue was dissolved in dichloromethane (20ml, dried over basic alumina) and the solution was brought to pH=8 withtriethyl amine.

Basic solution of 4-dimethylaminobenzoyl chloride was added dropwise tothe solution of 1,3-bis(triphenylmethanethio)-propane-2-ol (0.67 g,0.0011 mol) in dichloromethane (10 ml, dried over basic alumina) withtriethyl amine (0.2 ml, 0.0013 mol). The reaction mixture was stirred atambient temperature for 3 hours. Hexane (100 ml) was added to thereaction mixture. Organic layer was washed with aqueous methanol (30%methanol), dried over sodium sulfate anhydrous, and concentrated. Flashchromatography with hexane: dichloromethane (6:4) afforded the product(0.7 g, 84%).

1H NMR (250 MHz) δ ppm: 2.4 (abddd, 4H, J₁=J₂=6.5 Hz, CH₂), 4.75 (dd,1H, CH) 6.7 (d, 2H, J=9 Hz, Ar), 7.4 (m, 30H, 2×C(Ph)₃), 7.9 (d, 2H, J=9Hz, Ar).

Third Step:

To the solution of 1,3-bis(triphenylthio)-propane-2-ol derivative (0.7g, 0.0009 mol) in dichloromethane (5 ml), trifluoroacetic acid (1 ml)was added. The reaction mixture was stirred for 4 hours at ambienttemperature. The solvent was evaporated. The crude was dissolved indichloromethane-methanol. Freshly prepared 2N sodium methylate (0.9 ml)was added followed by addition of iodine (0.47 g). Flash chromatographywith hexane:ethyl acetate (6:4) afforded compound 4 (0.19 g, 78%).

1H NMR (300 MHz) δ ppm: 3.0 (s, 6H, N(CH₃)₂), 3.4 & 3.6 (abddd, 4H,J₁=1.8 Hz, J₂=8 Hz, J₃=62 Hz, CH₂), 5.8 (ddd, 1H, J=8 Hz, CH), 6.6 (d,2H, J=9.1 Hz, Ar), 7.9 (d, 2H, J=9.1 Hz, Ar).

Example 4 Synthesis of Compound (5)

First Step:

A suspension of sodium hydrogen sulfide (21 g, 0.375 mol) in methanol(150 ml was prepared. Epichlorohydrine (5 ml, 0.065 mol) in THF (20 ml)was added dropwise at room temperature. The flask was sealed and thereaction mixture was stirred overnight at room temperature. Methanol wasevaporated and the residue was dissolved in water (50 ml). Aqueous layerwas extracted with chloroform. Collected organic fractions were driedover sodium sulfate and concentrated. The residue was used for furtherstep without purification.

Second Step:

To the solution of 4-hydroxy-1,2-dithiolane (as a crude from thereaction between epichlorhydrine and sodium hydrogen sulfide) (0.1 g) indichloromethane (dried over basic alumina 10 ml) toluoyl chloride (0.14ml, 0.001 mol) was added followed by addition of triethylamine (0.23 ml,0.0016 mol). The reaction mixture was stirred overnight at ambienttemperature. Flash chromatography with hexane-ethyl acetate (4:6) aseluent afforded compound 5 (15 mg).

1H NMR (300 MHz) δ ppm: 2.4 (s, 3H, CH₃), 3.15 & 3.25 (abddd, 4H, J₁=3.8Hz, J₂=7.2 Hz, J₃=15 Hz, CH₂), 5.8 (ddd, 1H, J₁=3.8 Hz, J₂=7.1 Hz, CH),7.2 (d, 2H, J=8.2 Hz, Ar), 7.9 (d, 2H, J=8.2 Hz, Ar).

Example 5 Synthesis of O-benzoyl [1,2] dithiolan-4-ol (6)

Epichlorohydrin (3 ml, 0.029 mol) was added to a solution of NaSH (15 g,0.27 mol) in MeOH (115 ml). The solution was stirred at room temperatureover night. MeOH was evaporated, the residue was dissolved in brine(i.e. saturated aqueous NaCl solution), extracted several times withchloroform, dried with sodium sulfate, filtered and evaporated todryness. The product 4-hydroxy-1,2-dithiolane was not purified forfurther reaction.

Benzoyl chloride (1.4 ml) and triethyl amine (1.2 ml) were added to asolution of 4-hydroxy-1,2-dithiolane (as a crude from the reactionbetween epichlorhydrine and sodium hydrogen sulfide) (1 gr) in drydichloromethane (30 ml). The solution was stirred at room temperatureunder nitrogen over night. Dichloromethane was added to the solution,extracted several time with aqueous K₂CO₃ 5%, HCl 1N and Brine, driedover sodium sulfate, filtered and evaporated to dryness.

The product obtained was purified by a flash column chromatography ofSilica gel with dichloromethane:hexane (2:1) as eluent to give compound6 (0.25 gr.); NMR (CDCl₃, 250 MHz) δ=8.03 (m, 2H, Ar_(m)), 7.58 (m, 1H,Ar_(p)), 7.43 (m, 2H, Ar_(o)), 5.48 (m, 1H, SCH₂CHO), 3.21 (m, 4H,SCH₂CHO); IR (CHCl₃) ν=1734 cm⁻¹ (ester).

Example 6 Synthesis of Compound (7)

First Step:

(according to the procedure in Becker H. J., Tamsma A. F, Rec. Trav.Chim, 1938, 1183–1210).

A suspension of sodium hydrogen sulfide (10.7 g, 0.19 mol) in methanol(100 ml) was prepared. 2,2-Bis(bromomethyl)-1,3-propanediol (5 g, 0.019mol) in methanol (20 ml) was added dropwise at room temperature. Theflask was sealed and the reaction mixture was stirred for 18 hours atroom temperature and then refluxed for 2 additional hours. One third ofmethanol was evaporated and ethyl acetate was added (50 ml). Theprecipitate was filtered out and the procedure was repeated four timeswith supernatant. Ethyl acetate was evaporated. Recrystalization fromhot toluene afforded the product (1.6 g; 50%).

1H NMR (250 MHz, CD₃OD) δ ppm: 2.9 (s, 2H, CH₂S), 3.6 (s, 2H, CH₂O).

Second Step:

To the solution of 4,4-bis(hydroxymethyl)-1,2-dithiolane (0.15 g, 0.0009mol) in dichloromethane (dried over basic alumina 10 ml) benzoylchloride (0.23 ml, 0.002 mol) was added followed by addition oftriethylamine (0.29 ml, 0.002 mol). The reaction mixture was stirredovernight at ambient temperature. Flash chromatography withhexane-chloroform (6:4) as eluent afforded the product (120 mg, 35%).

1H NMR (300 MHz, CDCl₃) δ ppm: 3.2 (s, 2H, CH₂S), 4.5 (s, 2H, CH₂O), 7.4(dd, 2H, J₁=J₂=7.8 Hz, Ar), 7.55 (dd, 1H, J₁=J₂=7.8 Hz, Ar), 8.0 (d, 2H,J=7.8 Hz).

Example 7 Synthesis of Thioether Carbazido Compound (8)

The compound was synthesized via the following pathway:

First Step: Synthesis of I:

Anhydrous potassium carbonate was added to a solution of2-methyl-1-butanethiol in DMF. Bromo-ethylbutyrate was added and stirredover night.

The solution was dissolved in a mixture of hexane/ethyl acetate (1:3)and washed several times with water, dried over Na₂SO₄, filtered andevaporated to dryness. The product I may contain traces of the thiol.

Second Step: Synthesis of II:

The ester I was dissolved in MeOH (10 ml/mmol) and 1N NaOH (1.1 ml) andstirred for 1 hour. In a case that the reaction was not ended,additional aliquot of NaOH was added. After the consumption of theester, MeOH was evaporated, the residue was dissolved in water andwashed with EtOAc. The basic aqueous solution was acidified with KHSO₄1M to pH 4. The product was extracted several times with EtOAc, driedover Na₂SO₄, filtered and evaporated to dryness. The overall yield ofthe two steps is close to quantitative.

NMR (CDCl₃, 250 MHz) δ=2.5 (m, 6H, three methylene groups), 1.85 (m, 2H,SCH₂CH₂CH₂), 1.47 (m, 2H, CH₃CH₂CH(CH₃)), 1.18 (m, 1H, CH₃CH₂CH(CH₃)),0.94 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.87 (d, J=7 Hz, 3H,CH₃CH₂CH(CH₃)). IR (CHCl₃) ν=1715 cm⁻¹ (COOH).

Third Step: Synthesis of III:

Oxalyl chloride (4.5 ml) and a few drops of DMF were added to a solutionof the acid II (1.6 gr.) in dry dichloromethane and kept under inertatmosphere over night. The solvents were removed in vacuo, the residuewas dissolved in dry dichloromethane and introduced in a dropping funnelunder nitrogen stream. The acyl chloride was added dropwise to asolution of p-phenylene diamine in DMF (3.5 ml in 15 ml DMF) and themixture was stirred for two hours. Chloroform was added and the organicsolution was washed with water and dried. The product was purified byflash column chromatography (chloroform:MeOH 95:5 as eluent) to givepure product. (900 mg, 40%).

NMR (CDCl₃, 250 MHz) δ=7.5(b, 1H, CONHAr), 7.25+6.6 (Abq, 4H, Ar) 2.5(m, 6H, three methylene groups), 1.95 (m, 2H, SCH₂CH₂CH₂), 1.5 (m, 2H,CH₃CH₂CH(CH₃)), 1.2 (m, 1H, CH₃CH₂CH(CH₃)), 0.94 (d, J=6.5 Hz, 3H,CH₃CH₂CH(CH₃)), 0.87 (d, J=7 Hz, 3H, CH₃CH₂CH(CH₃)). IR (CHCl₃) ν+1670cm⁻¹ (CONH).

Fourth Step: Synthesis of IV:

Triphosgene (400 mg.) and 2,6 lutidine (1 ml) were added to a solutionof the free amine III (900 mg) in dry dichloromethane under inertatmosphere and stirred for 10 min. t-Bu-carbazate (500 mg) was added andthe mixture was left for an hour. Chloroform was added and the organicsolution was washed with NaHCO₃ 1N, HCl 1N, water and dried. The productwas purified by flash column chromatography (chloroform:MeOH 95:5 aseluent) to give 700 mg almost pure product IV. The product wasrecrystalized from MeOH/ether to give of pure IV (500 mg., 35%). NMR(CDCl₃, 250 MHz) δ=8.27 (b, 1H, NHNHBoc), 7.79 (b, 1H, NHNHBoc), 7.4 (b,1H, CONHAr), 7.7 (m, 4H, Ar), 2.5 (m, 6H, three methylene groups), 1.98(m, 2H, SCH₂CH₂CH₂), 1.5 (m, 11H, Boc+CH₃CH₂CH(CH₃)), 1.2 (m, 1H,CH₃CH₂CH(CH₃)), 0.97 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.88 (d, J=7 Hz,3H, CH₃CH₂CH(CH₃)). IR (CHCl₃)) ν=1670 cm⁻¹ (CONH), 1710 cm⁻¹ (Boc).

Last Step: Synthesis of 8:

The boc-protected semicarbazide IV (160 mg.) prepared above was treatedwith 15% TFA in dichloromethane over night, the solvent was removed, theresidue was treated with triethylamine (in methanol) to obtain neutralpH, dried, and purified by flash column chromatography (chloroform:MeOH95:5 as eluent) to give of product 8. (100 mg, 80%).

NMR (MeOD+CDCl₃, 250 MHz) δ=7.4 (m, 4H, Ar), 2.45 (m, 6H, threemethylene groups), 1.92 (m, 2H, SCH₂CH₂CH₂), 1.4 (m, 2H, CH₃CH₂CH(CH₃)),1.1 (m, 1H, CH₃CH₂CH(CH₃)), 0.89 (d, J=6.5 Hz, 3H, CH₃CH₂CH(CH₃)), 0.83(d, J=7 Hz, 3H, CH₃CH₂CH(CH₃)).

Example 8 Synthesis of Acetanilide Derivatives 9 and 10

The acetanilide derivatives 9 and 10 were synthesized in a three-stepprocedure, as showed below:

Compound 9: R=(CH₂)₇CH₃, n=2

The first two steps are identical to those of the synthesis of compound8. Oxalyl chloride (5 ml) and a few drops of DMF were added to asolution of the acid VI (0.8 gr.) in dry dichloromethane and kept underinert atmosphere over night. The solvents were removed in vacuo, theresidue was dissolved in dry dichloromethane. p-Amino acetanilide (0.8gr.) and triethylamine (1 ml) were added to the solution and stirred atroom temperature for additional 3 hours. The solution was washed withHCl 1N and aqueous K₂CO₃ (5%), dried over MgSO₄ followed by columnpurification (chloroform:ethyl acetate 1:1 as eluent) to provide purecompound 9. (400 mg., 31%)

NMR (CDCl₃, 250 MHz) δ=7.58 (b, 1H, NH), 7.45 (s, 4H, Ar), 7.17 (b, 1H,NH), 2.89 (t, J=7 Hz, 2H, CH₂CO) 2.56 (m, 4H, CH₂SCH₂), 2.17 (s, 3H,COCH₃), 1.25 (m, 12H, CH₃(CH₂)₆(CH₂), 0.87 (bt, 3H, CH₃(CH₂)₆CH₂).

Synthesis of Compound (10): R=(CH₂)₃CH₃, n=3

The first two steps are identical to those of the synthesis of compound8. Oxalyl chloride (10 ml) and a few drops of DMF were added to asolution of the acid VI (2.6 gr.) in dry dichloromethane and kept underinert atmosphere over night. The solvents were removed in vacuo, theresidue was dissolved in dry dichloromethane. p-Amino acetanilide (2gr.) and triethylamine (2 ml) were added to the solution and stirred atroom temperature for additional 3 hour. The solution was washed with HCl1N and aqueous K₂CO₃ (5%), dried over MgSO₄ followed by columnpurification (methylene chloride:ethyl acetate 1:1 as eluent) to providepure compound 10. (800 mg., 18%)

NMR (CDCl₃, 250 MHz) δ=7.46 (s, 4H, Ar), 7.25 (b, 1H, NH), 7.15 (b, 1H,NH), 2.60 (t, J=7 Hz, 2H, CH₂CO) 2.5 (m, 4H, CH₂SCH₂), 2.17 (s, 3H,COCH₃), 2.05 (m, 2H, CH₂CH₂CO), 1.42 (m, 4H, CH₃(CH₂)₂CH₂), 0.91 (t, J=7Hz, 3H, CH₃(CH₂)₂CH₂).

Example 9 Affinity and Selectivity Experiments

The following receptor molecules have been tested:

The affinity and selectivity of the receptors 4–10 and of a fewpolymeric receptors were examined in the following way:

i—A 250 MHz quartz crystal resonator was first modified with a monolayercomprising one of the artificial receptors 4–10.

ii—Three analytes were checked: TATP, Naphthalene and2,3-dimethyl-2,3-dinitrobutane, each having a specific vapor pressure.

iii—The frequency change of the resonator due to the exposure to thevapor of ˜100 μg of the analyte at room temperature in a 2 cc chamberwas recorded within 60 sec.

The following table summarizes the maximum response (measured in Hz) ofsome modified resonators to the tested analytes:

Compound TATP Naphthalene DDB 4 1370 2500 380 5 720 700 230 6 6950 1900250 7 4750 2520 300 8 300 1000 80 9 650 1080 230 10  4200 1350 780Polyfluorene 1100 2100 420 Polypyrrole 1500 2900 320 Poly (N-methyl 13001950 130 aniline)

Example 10 Detection of Iohexole in Liquid Environment

The boronic acid derivative 11 synthesized for the detection of iohexolein solution has the following structure:

Iohexole is a compound used as a source for iodine needed for CT scans.However, the secretion of iohexole in the urine may also indicatecertain gastro diseases.

The boronic acid derivative was prepared according to the followingscheme:

a) Synthesis of p-bromomethyl phenyl boronic acid—neopentyl ester (VIIand VIII)(according to the procedure in Nakao H. et al. Biosci. Biotech. Biochem.60(4) 1996, 683–684.)

p-Toluene boronic acid (750 mg.) and neopentyl glycol (600 mg.) weredissolved in 50 ml cyclohexane and heated at reflux for 1.5 hours.N-Bromosuccinimide (1.15 g.), benzoyl peroxide (25 mg.) and 150 mlcyclohexane were added and the solution was heated at reflux foradditional 2 hours. The solution was cooled to room temperature,filtered and evaporated to give a mixture of VII and VIII (total of 1.3g,˜1:1 ratio), the yield=47%.

NMR (CDCl₃, 250 MHz) δ=7.81+7.38 (Abq, 4H, Ar), 5.50 (s, 2H, ArCH₂Br),3.77 (s, 4H, OCH₂C), 1.03 (s, 6H, C(CH₃)₂).

b) Synthesis of IX:

Anhydrous potassium carbonate was added to a solution of 1-butanethiol(90 μl) in DMF. A (450 mg.) was added and the mixture was stirred overnight.

The solution was dissolved in a mixture of hexane/ethyl acetate (1:3)and washed several times with water, dried over Na₂SO₄, filtered andevaporated to dryness. The product was purified by flash columnchromatography (ethyl acetate: dichloromethane 4:6 as eluent).Yield=15%.

NMR (CDCl₃, 250 MHz) δ=7.72+7.27 (Abq, 4H, Ar), 3.74 (s, 4H, OCH₂C),3.68 (s, 2H, ArCH₂S) 2.40 (m, 2H, SCH₂CH₂CH₂CH₃), 1.54 (m, 2H,SCH₂CH₂CH₂CH₃), 1.31 (m, 2H, SCH₂CH₂CH₂CH₃), 1.00 (s, 6H, C(CH₃)₂), 0.85(t, J=7 Hz, 3H, SCH₂CH₂CH₂CH₃).

c) Synthesis of 11

The boronic ester IX (50 mg.) was hydrolyzed in THF/HCl 2N (1:1) overnight at room temperature. The THF was evaporated, the residue wasdissolved in ethyl acetate, washed with water and purified by threeconsequence chromatography columns ((i) CHCl₃:MeOH 97:3, (ii) CHCl₃:MeOH99:1, n-Hexane:Ethyl acetate (gradient from 20% to 50% ethyl acetate)).Yield=15%.

NMR (CDCl₃, 250 MHz) δ=7.20+6.73 (Abq, 4H, Ar), 3.65 (s, 2H, ArCH₂S)2.43 (m, 2H, SCH₂CH₂CH₂CH₃), 1.28 (m, 4H, SCH₂CH₂CH₂CH₃), 0.88 (t, J=7Hz, 3H, SCH₂CH₂CH₂CH₃).

Measurements were performed with 30 MHz resonators in water. Theresponse of a resonator coated with the boronic acid derivative 11, indistilled water, was compared to that of a 25 μg/ml solution of iohexoleas an analyte.

The response of the resonator to the iohexole solution was in the rangeof 600 Hz.

Those skilled in the art will readily appreciate that variousmodification and changes can be applied to the embodiments of theinvention as hereinbefore described and exemplified without departingfrom its scope defined in and by appended claims.

1. A piezoelectric crystal element for use in a sensor device foridentifying at least one foreign material from environment, the crystalelement comprising at least one crystal resonator in the form of aninverted mesa structure having a membrane-like region, which issubstantially thinner as compared to end portion of the crystalresonator surrounding said membrane-like region and has a certainresonance frequency value, a surface region of said at least one crystalresonator being modified by reactive molecules of a kind capable ofinteracting with said at least one foreign material to yield a reactionproduct that effects a change in the resonance frequency of saidmembrane-like region from said certain resonance frequency value, saidchange being indicative of the identity and quantity of said at leastone foreign material.
 2. The element according to claim 1, wherein saidat least one crystal resonator is a quartz crystal.
 3. The elementaccording to claim 1, wherein said at least one membrane-like region hasa thickness of about several micrometers.
 4. The element according toclaim 1, wherein the membrane-like region of the at least one crystalresonator is coated with metal electrodes on opposite sides thereof,said electrodes being made of metal selected from Au, Pt and Al.
 5. Theelement according to claim 4, wherein said electrodes are made of Au. 6.The element according to claim 4, wherein an Au-based glue is used forattaching the crystal element to a holder.
 7. The element accordingclaim 1, further comprising at least one additional crystal resonator inthe form of an inverted mesa structure having a membrane-like regionsubstantially thinner as compared to end portion of the additionalcrystal resonator surrounding said membrane-like region, and having asurface region modified by reactive molecules of a kind capable ofinteracting with a foreign material of the environment to yield areaction product that effects a change in the resonance frequency of theadditional membrane-like region.
 8. The element according to claim 7,comprising an array of spaced-apart crystal resonators, each resonatorbeing in the form of an inverted mesa structure formed with a pair ofelectrodes at opposite sides of the membrane-like region thereof andhaving the modified surface region, thereby defining an array of sensingregions excitable by the environment to produce the changes in thefrequencies of crystal resonators.
 9. The device according to claims 8,wherein a distance between each of the crystal resonators and itsassociated oscillator of the actuator utility is the same for all thecrystal resonators.
 10. The device according to claim 9, wherein thecrystal resonators are arranged in spaced-apart relationship along acircular path, and are associated with the common oscillator located ona central axis of the circle.
 11. The device according to claim 9,wherein the piezoelectric crystal element comprises a disc formed with acircular array of the piezoelectric quartz crystal resonators, and theactuator utility comprises the oscillator located in the center of thedisc and associated with all the crystal resonators.
 12. The deviceaccording to claim 9, wherein the piezoelectric crystal elementcomprises a disc formed with a circular array of the piezoelectricquartz crystal resonators, and the actuator utility comprises aplurality of oscillators located on said disc, each of the oscillatorsbeing associated with a corresponding one of the oscillators.
 13. Theelement according to claim 7, wherein the surface regions of differentcrystal resonators are modified with different reactive molecules,thereby enabling detection of various foreign materials contained in theenvironment.
 14. A piezoelectric sensor for use in a device foridentifying at least one foreign material from environment, thepiezoelectric sensor comprising the piezoelectric crystal element of anyone of preceding claims with electrodes formed on opposite sides of saidat least one membrane-like sensing region.
 15. A piezoelectric sensordevice for identifying at least one foreign material from environment,the device comprising the sensor of claim 14, and a control meansoperable for actuating said at least one crystal resonator, measuringthe change in the resonance frequency of said at least one membrane-likeregion, and generating measured data indicative of the identity andquantity of said at least one foreign material.
 16. The device accordingto claim 15, wherein the control means comprises an actuator utility foroperating said at least one crystal resonator, and a detector utilityfor detecting the frequency of said at least one membrane-like region toenable the measurement of said change.
 17. The piezoelectric crystalelement according claim 1, wherein said reactive molecules form anorganized, self-assembled monolayer (SAM), said monolayer consisting ofreceptor compounds comprising a linker that connects said compound tothe surface of said substrate, an optional spacer, a structural elementand an active head group.
 18. The piezoelectric crystal elementaccording claim 1, wherein said surface region of said at least onecrystal resonator is modified by a polymeric layer.
 19. Thepiezoelectric crystal element according to claim 18, wherein saidpolymeric layer comprises at least one polymeric material selected fromthe group consisting of: polypyrrole, polythiophene, polytriphenylene,poly(dimethylamino)pyrrole, polyaniline, poly(N-phenyl)aniline,poly(N-methyl)aniline, polyfluoroaniline, polypyrene, polyfluorene andpolyfluoranthene.